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Malaria Parasite Development, Drug Resistance, Pathogenesis, and Genomics

疟疾寄生虫的发育、耐药性、发病机制和基因组学

基本信息

批准号：
9563887
负责人：
Xinzhuan Su
金额：
$ 152.01万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9563887
关键词：
Antimalarials Binding Biochemical Birds CRISPR/Cas technology Cell physiology China Code Collaborations Communication DNA Development Disease Drug resistance FOSL1 gene Genes Genetic Genomic approach Genomics Goals Growth Immune response Immunity Infection Inflammation Inflammatory Response Interferon Type I Interferon Type II Interferons Interruption Malaria Manuscripts Mediating Methodist Church Methods Molecular Myanmar Nature Parasitemia Parasites Parasitology Pathogenesis Plasmodium falciparum Plasmodium yoelii Play Prevalence Study Publishing RNA Reporting Research Institute Resistance Role Scientist Signal Pathway Signal Transduction TBK1 gene TNF receptor-associated factor 3 TNFRSF5 gene Testing Ubiquitin Universities Virulence Virus Diseases Work cell type disease mechanisms study disease phenotype functional genomics genetic approach genome wide association study immune function malaria infection mouse model pathogen response transcription factor transmission process ubiquitin-protein ligase

项目摘要

During the year of 2016-2017, we focused on studying molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii/mouse model. We have made good progresses in several projects: 1. We finished a project studying the role of CD40 in regulating type I interferon (IFN-I) response during malaria infection. We showed that CD40 could enhance STING-stimulated IFN-I response and played a role in parasitemia control and host survival. We also showed that parasite materials such as DNA and RNA could stimulate CD40 expression through TLR signaling pathways. This study reveals a previously unrecognized function of CD40 in innate IFN-I responses and provides important information for better understanding and management of malaria. This work was published in PLoS Pathogens. 2. We have also finished functional verification of a parasite E3 ubiquitin ligase in regulating parasite growth and disease virulence. We replaced partial coding sequences of the E3 ubiquitin liagse gene using the CRISPR/cas9 method. We showed changed parasite growth after exchange of partial gene sequences, which confirms a role of the gene in parasite development and disease virulence. A manuscript has been accepted by Nature Communications. 3. We continued to study the molecular mechanism of inflammatory responses after P. yoelii infection. We are now focusing on pro-inflammatory responses mediated by IFN-gamma and are dissecting the molecular interactions and cell types contributing to inflammation after parasite infection. A manuscript has been submitted to Scientific Reports. 4. We have made good progresses on other projects, including a gene called March1. We found that this gene can regulate host response to infections of multiple parasite strains. We are investigating the molecular mechanism of how this gene regulates host immune response. 5. Additionally, in collaboration with scientists at Houston Methodist Research Institute, Houston, we have identified a critical regulatory mechanism of IFN-I signaling in pDCs and stage-specific function of immune cells in generating potent immunity against a lethal malaria infection, which was published in Immunity. 6. In a second collaborative project, we discovered a previously unknown role of the transcription factor FOSL1 in regulating IFN-I response. We showed that FOSL1 could inhibit IFN-I responses to malaria and viral infections by blocking TBK1 and TRAF3/TRIF Interactions. This work was published in mBio. 7. In collaboration with scientists at Penn State University, we used genome-wide association analysis to identify genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum parasites collected from China-Myanmar border. This work was published in Scientific Reports. 8. In collaboration with scientists at Xiamen University, we continued to study prevalence of a bird parasite (Leucocytozoon sabrazesi) in Southern China. We also tested several tricyclic compounds against the gametocyte of the parasite. The work was published in PLoS ONE. 9. In a second collaborative project, we developed a CRISPR/Cas9 method that allows sequential editing of Plasmodium yoelii genes, which was published in Molecular and Biochemical Parasitology.

2016-2017年，我们主要利用约氏疟原虫/小鼠模型研究疟疾发病的分子机制和信号通路。